Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177.Most activating EGFR gene mutations in lung cancer are amenable to EGFR tyrosine kinase inhibitors (TKI). Whereas mutations in exons 19 and 21 are sensitive, exon 20 insertion mutations are mostly resistant. Yasuda and colleagues identified an exon 20 mutation (EGFR A763_Y764insFQEA) as responsive to EGFR TKIs. This sensitizing mutation differs from other exon 20 insertions, causing a shift of the C-helix toward its N-terminus, reminiscent of the sensitive L858R and exon 19 deletion mutants. In contrast, resistant exon 20 insertion mutations lock the C-helix in its active position, blocking binding of EGFR TKIs. This differs substantially from the EGFR T790M mutation, which confers resistance by altering the gatekeeper residue in the ATP site, presenting a tricky drug discovery problem.Dash R, Bhoopathi P, Das SK, Sarkar S, Emdad L, Dasgupta S, et al. Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res 2014;74:563–74.Driving tumor cells to die represents a promising therapy. MDA-7/IL-24, an IL-10 family cytokine, and SARI (suppressor of AP-1), a novel type I IFN-inducible early response gene, were cloned using subtraction hybridization and induction of differentiation. MDA-7/IL-24 drove expression of SARI, inhibiting cancer cells while sparing normal cells. Genetically, SARI was a downstream target of mda-7/IL-24 and was indispensable for mda-7/IL-24–mediated tumor cell death. Inhibition of p38 MAPK abrogated expression of SARI in response to mda-7/IL-24, confirming the role of p38 MAPK in cancer cell death. This study by Dash and colleagues clarifies cross-talk between mda-7/IL-24 and SARI in tumor-specific cell death and opens up new therapeutic avenues.Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G, et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 2014;343:72–6.In glioblastoma, amplified EGFR commonly exists on extrachromosomal double minute chromosomes. In an analysis of paired pre- and posttreatment tumors, Nathanson and colleagues show (by FISH) that the decreased expression of tumor-derived EGFRvIII following EGFR tyrosine kinase inhibitors (TKI) is due to a selective and reversible loss of EGFRvIII on extrachromosomal DNA. Tumors generated from sorted populations of EGFRvIII high or EGFRvIII low cells restored their presorted proportion of EGFRvIII high tumor cells. While therapy may also select for a subpopulation of low-level EGFR-amplified tumor cells, loss of extrachromosomal DNA fragments containing EGFR may represent an important mechanism of resistance to EGFR TKI and suggests modified dosing strategies to circumvent such resistance.Shin S, Wolgamott L, Roux PP, Yoon SO. Casein kinase 1ϵ promotes cell proliferation by regulating mRNA translation. Cancer Res 2014;74:201–11.The mRNA cap-binding protein 4E-BP1 (EIF4BP1) binds to eIF4E to inhibit translation initiation. Shin and colleagues identify casein kinase 1ϵ (CK1ϵ, CSNK1E) as a novel regulator of 4E-BP1. CK1ϵ, expressed highly in breast cancer, is required for proliferation of breast cancer cells in vitro and in vivo. CK1ϵ binds to and phosphorylates 4E-BP1 at sites distinct from those utilized by mTORC1, another important regulator of cap-dependent translation. Furthermore, the reduced proliferation resulting from decreased CK1ϵ activity was 4E-BP1 dependent, as attenuation of growth was not observed in MEFs lacking 4E-BP1 and 2. The authors thus propose CK1ϵ as a novel therapeutic target for cancers driven by deregulated mRNA translation.Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, et al. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 2014;46:33–8.Drivers of tumorigenesis are difficult to identify if they involve low-frequency somatic mutations. Wong and colleagues address this challenge by identifying genes with an increased ratio of observed to expected nonsense mutations in a set of ∼8,000 cancer genome sequences derived from 28 tumor types. The 54 identified genes included known drivers of tumorigenesis CDKN2A, TP53, and PTEN, thereby validating this approach. Focusing exclusively on the transcription factor CUX1 (cut-like homeobox 1), inactivation of which occurs in &lt;5% of cancers surveyed, the authors show that loss of CUX1 activates PI3K via downregulation of the PI3K inhibitor PIK3IP1. This study identifies CUX1 as a driver of cancer and suggests PI3K inhibitors as a therapy.Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013;504:296–300.The role of autophagy in cancer is controversial, as autophagy has been shown to both enhance and suppress tumor development. Using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC), Rosenfeldt and colleagues demonstrate that Trp53 dictates whether autophagy enhances or suppresses tumor development. Mice expressing oncogenic Kras developed precancerous lesions, progressing over time to PDAC. However, Kras-mutant mice lacking essential autophagy regulators Atg5 or Atg7 never developed PDAC, consistent with a tumor-suppressive role for autophagy. Removal of Trp53 along with Atg5 or Atg7 led to enhanced Kras-driven tumorigenesis. Interestingly, Kras;Trp53-mutant mice also showed enhanced tumorigenesis upon treatment with hydroxychloroquine, a lysosomal inhibitor of autophagy currently in clinical trials for cancer.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.